The interaction between hepatocytes and collagen may be of importance in the pathogenesis of chronic hepatocellular disease. The adherence of each of the five types of collagen to hepatocytes isolated from normal rats and rats with carbon tetrachloride-induced hepatic fibrosis has been studied. Attachment of hepatocytes from normal rats was enchanced four-fold by the presence of either serum or fibronectin, the glycoprotein required for fibroblast attachment to collagen. In the absence of serum or fibronectin, hepatocytes adhered best to basement membrane collagen (type IV). This phenomenon was abolished by sodium periodate oxidation of collagen, suggesting that hepatocytes were attached to collagen by recognizing a specific carbohydrate residue. Hepatocytes isolated from rats with hepatic fibrosis bound less avidly to collagen than those from normal rats. Neither hepatocytes from normal rats nor those from rats with hepatic fibrosis appear to synthesize collagen in vitro. These studies indicate a defect in the interaction of hepatocytes with collagen in an animal model of chronic liver disease.